The project builds upon the largest case control study of bladder cancer (BC) in U.S. with extensive epidemiologic and clinical data and rich biospecimens (DNA, fissue, and serum/plasma). We propose a systemafic study of microRNAs (miRNAs) in BC efiology, prognosis, and BCG response, including germline SNP genotyping, somafic miRNA profiling, and detecfion of circulafing miRNA. Our specific aims are: 1) To identify novel germline suscepfibility loci in miRNA pathway that predispose to BC risk using a two-stage design. We will screen -8000 SNPs in 1000 cases and 1000 controls and then validate top 384 SNPs in an addifional 1000 cases and controls. 2) To identify novel germline suscepfibility loci in miRNA pathway that predict non-muscle invasive BC (NMIBC) recurrence and progression using a similar twostage design as in Aim 1. In screening phase, we will use 1,200 NMIBC patients from our ongoing case control study. We will also performed stratified analysis on those patients receiving BCG treatment since BCG is the prevalent intravesical therapy for high risk NMIBC. In the validation phase, we will use 300 patients who were enrolled in a clinical trial of BCG treatment. 3) To identify somatic miRNA expression as predictors of BCG response. We will determine global miRNA expression profiles in 50 BC tumor tissues with recurrence and 50 without recurrence in patients receiving BCG treatment to idenfify somatic miRNA signature that predicts recurrence and then validate the signatures in an addifional 75 pairs of tissues. We will also correlate the validated SNPs from Aim 2 with the expression of validated miRNAs from this aim. 4) To identify circulating miRNAs as predictors of recurrence and progression in NMIBC patients receiving BCG treatment. Similar to Aim 3, we will use a two stage design to idenfify and validate miRNA signatures for recurrence and progression in the context of BCG treatment. Screening will be done in serum of 100 BCG-treated NMIBC patients with and 100 pafients without recurrence, and in 50 BCG-treated NMIBC patients with and 50 pafients without progression, and validation will be done using 300 pafients enrolled in the BCG clinical trial.